Midazolam ameliorates the behavior deficits of a rat posttraumatic stress disorder model through dual 18 kDa translocator protein and central benzodiazepine receptor and neurosteroidogenesis.

Post-traumatic stress disorder (PTSD) is a debilitating anxiety disorder that may develop after an individual has experienced or witnessed a severe traumatic event. It has been shown that the 18 kDa translocator protein (TSPO) may be correlated with PTSD and that the TSPO ligand improved the behavioral deficits in a mouse model of PTSD. Midazolam, a ligand for TSPO and central benzodiazepine receptor (CBR), induces anxiolytic- and anti-depressant-like effects in animal models. The present study aimed to determine whether midazolam ameliorates PTSD behavior in rats as assessed by the single prolonged stress (SPS) model. The SPS rats received daily Sertraline (Ser) (15 mg/kg, i.p.) [corrected] and midazolam (0.125, 0.25, 0.5, and 1 mg/kg, i.p.) [corrected] during the exposure to SPS and behavioral assessments, which included the open field (OF) test, the contextual fear paradigm (CFP), and the elevated plus-maze (EPM). The results showed that, like Ser (15 mg/kg, i.p.) [corrected], midazolam (0.25 and 0.5 mg/kg, i.p.) [corrected] significantly reversed the behavioral deficiencies of the SPS rats, including PTSD-associated freezing and anxiety-like behavior but not the effects on spontaneous locomotor activity. In addition, the anti-PTSD effects of midazolam (0.5 mg/kg, i.p.) [corrected] were antagonized by the TSPO antagonist PK11195 (3 mg/kg, i.p.), the CBR antagonist flumazenil (15 mg/kg, i.p.) [corrected] and the inhibitor of steroidogenic enzymes finasteride (30 mg/kg, i.p.) [corrected], which by themselves had no effect on PTSD-associated freezing and anxiety-like behavior. In summary, this study demonstrated that midazolam improves the behavioral deficits in the SPS model through dual TSPO and CBR and neurosteroidogenesis.

Clinical effectiveness of gene therapy on critical limb ischemia: a meta-analysis of 5 randomized controlled clinical trials.

Therapeutic angiogenesis using gene therapy is a novel strategy for the treatment of critical limb ischemia (CLI). We conducted a meta-analysis to evaluate the efficacy and safety of gene therapy for the treatment of CLI with no option of revascularization. Randomized placebo controlled trials of gene therapy on CLI were identified by searching PubMed (from 1990 to October 2013) and EMBASE (from 1990 to October 2013). Five eligible studies were selected for the meta-analysis. Among these studies, a total of 425 patients received gene therapy of either fibroblast growth factor 1 or hepatocyte growth factor, and 365 patients were given placebo. No statistical differences were observed between the 2 groups in major amputation or death at 1 year (risk ratio [RR], 0.83; 95% confidence interval [CI], 0.51-1.39; P = .48) and wound healing at 6 months (RR, 1.55; 95% CI, 0.73-3.28; P = .25). Gene therapy had similar occurrence of serious adverse events as control (RR, 1.05; 95% CI, 0.97-1.14; P = .23).

Leptin reverses corticosterone-induced inhibition of neural stem cell proliferation through activating the NR2B subunits of NMDA receptors.

Corticosterone inhibits the proliferation of hippocampal neural stem cells (NSCs). The removal of corticosterone-induced inhibition of NSCs proliferation has been reported to contribute to neural regeneration. Leptin has been shown to regulate brain development, improve angiogenesis, and promote neural regeneration; however, its effects on corticosterone-induced inhibition of NSCs proliferation remain unclear. Here we reported that leptin significantly promoted the proliferation of hippocampal NSCs in a concentration-dependent pattern. Also, leptin efficiently reversed the inhibition of NSCs proliferation induced by corticosterone. Interestingly, pre-treatment with non-specific NMDA antagonist MK-801, specific NR2B antagonist Ro 25-6981, or small interfering RNA (siRNA) targeting NR2B, significantly blocked the effect of leptin on corticosterone-induced inhibition of NSCs proliferation. Furthermore, corticosterone significantly reduced the protein expression of NR2B, whereas pre-treatment with leptin greatly reversed the attenuation of NR2B expression caused by corticosterone in cultured hippocampal NSCs. Our findings demonstrate that leptin reverses the corticosterone-induced inhibition of NSCs proliferation. This process is, at least partially mediated by increased expression of NR2B subunits of NMDA receptors.

The efficacy and cost-effectiveness of cell saver use in instrumented posterior correction and fusion surgery for scoliosis in school-aged children and adolescents.

Posterior spinal instrumentation and fusion surgery in school-aged children and adolescents is associated with the potential for massive intraoperative blood loss, which requires significant allogeneic blood transfusion. Until now, the intraoperative use of the cell saver has been extensively adopted; however, its efficacy and cost-effectiveness have not been well established. Therefore, the aim of this study is to determine the efficacy and cost-effectiveness of intraoperative cell saver use. This study was a single-center, retrospective study of 247 school-aged and adolescent patients who underwent posterior spinal instrumentation and fusion surgery between August 2007 and June 2013. A cell saver was used intraoperatively in 67 patients and was not used in 180 patients. Matched case-control pairs were selected using a propensity score to balance potential confounders in baseline characteristics. Allogeneic red blood cell (RBC) and plasma transfusions as well as blood transfusion costs were analyzed. The propensity score matching produced 60 matched pairs. Compared to the control group, the cell saver group had significantly fewer intraoperative allogeneic RBC transfusions (P = 0.012). However, when the combined postoperative and total perioperative periods were evaluated for the use of allogeneic RBC transfusion, no significant differences were observed between the two groups (P = 0.813 and P = 0.101, respectively). With regard to the total cost of perioperative transfusion of all blood products (RBC and plasma), costs for the control group were slightly lower than those of the cell saver group, but this variance did not reach statistical significance (P = 0.095). The use of the cell saver in posterior spinal instrumentation and fusion surgery in school-aged children and adolescents was able to decrease the amount of intraoperative allogeneic RBC transfusion but failed to decrease total perioperative allogeneic RBC transfusion. Moreover, the use of the cell saver was not cost-effective.

Midazolam provides cytoprotective effect during corticosterone-induced damages in rat astrocytes by stimulating steroidogenesis.

Midazolam is a benzodiazepine derivative drug that has powerful anxiolytic, amnestic, hypnotic, and sedative properties. The cytoprotective effect of midazolam on brain astrocytes is poorly understood. This study aimed to investigate the cytoprotective effect of midazolam on astrocytes exposed to corticosterone, a stress-produced glucocorticoid. We found that midazolam stimulated pregnenolone and progesterone secretion in astrocytes in a dose-dependent manner. Midazolam protected astrocytes from corticosterone-induced damages in a dose-dependent manner. In addition, we demonstrated that progesterone reduced corticosterone-induced damages. Finally, we applied trilostane, an inhibitor of 3ß-hydroxysteroid dehydrogenase, to inhibit pregnenolone metabolism and found that pretreatment with trilostane significantly inhibited the cytoprotective effect of midazolam on corticosterone-induced cytotoxicity in rat astrocytes in a dose-dependent manner. Taken together, these results demonstrate that midazolam has cytoprotective effect on astrocytes. This is, at least partially, derived from midazolam-induced steroidogenesis including progesterone and downstream products in astrocytes. Our data provide new insights into the cytoprotective effect of midazolam.

Surgical trauma induces iron accumulation and oxidative stress in a rodent model of postoperative cognitive dysfunction.

Postoperative cognitive dysfunction (POCD) is recognized as a complication after surgery in the elderly. The exact pathogenic mechanisms of POCD are still unknown. In this study, we investigated the role of iron accumulation within the central nervous system in the development of cognitive dysfunction in rats following splenectomy. Cognitive function was assessed using a Morris water maze on postoperative days 1, 3, and 7. Impaired cognitive function was observed on days 1 and 3 after splenectomy, while an anesthesia-alone group showed no significant difference from the control. Serum iron levels decreased and brain iron content increased on days 1 and 3 after surgery, which was in parallel with the impairment of cognitive function. Furthermore, the levels of proteins involved in the maintenance of brain iron homeostasis, including ferritin, transferrin receptor 1, and iron regulatory protein 2, were significantly different at postoperative days 1 and 3 in the hippocampus of splenectomized animals when compared with those of the control. The alterations in iron homeostasis were accompanied by intensified oxidative stress as measured by increases in the lipid peroxidation product, malondialdehyde, and a decrease in the levels of superoxide dismutase activity. Overall, these findings suggest that the impaired cognitive function was primarily due to surgical trauma rather than anesthesia. Increased iron accumulation and oxidative stress in the brain, especially in the hippocampus, may be involved in the pathogenesis of POCD.

[Effect of alpha-melanocyte stimulating hormone on the apoptosis of the vascular endothelial cell of the lung in two-hit acute respiratory distress syndrome in rat].

OBJECTIVE: To investigate the effect of alpha-melanocyte stimulating hormone (alpha-MSH) on the apoptosis of the vascular endothelial cells of the lung in acute respiratory distress syndrome (ARDS) reproduced with acute hemorrhagic shock followed by intratracheal lipopolysaccharide (LPS, two-hit model) in rat. METHODS: Ten male Sprague Dawley rats, weighing (33.7+/-2.5) g, were randomly divided into two groups (A and B) with 5 in each group. All rats were anesthesized and ventilated mechanically with fractional concentration of inspired oxygen(FiO(2)) of 0.5, breath rate 100 times/min, tidal volume(V(T)) 12 ml/kg and inspiratory/expiratory ratio (I/E) 1:15. The blood was withdrawn to induce hemorrhagic shock via the carotid artery until blood pressure reached (45+/-5) mm Hg (1 mm Hg=0.133 kPa), which was maintained for 1 hour, and the shed blood and Ringer's lactate in volume equal to the shed blood were reinfused in 2 hours for resuscitation. Afterwards, LPS was given via the tracheal (200 microg/kg, in 500 microl normal saline) to establish the ARDS model. Group A was ARDS control group, group B was alpha-MSH administration group. alpha-MSH was intravenously administrated simultaneously, 3 hours and 6 hours after LPS given, the dosage was 17 mg/kg at each time point. The rats were sacrificed at 9 hours after LPS challenge, and the lung tissue was examined with microscope and electron microscope to observe the pathological changes and apoptosis of the vascular endothelial cells. RESULTS: In ARDS control group, remarkable infiltration of inflammatory cells was found in the alveoli, and the apoptosis of the vascular endothelial cells had developed to late stage. In alpha-MSH treatment group, few inflammatory cells were found in the alveoli, and the apoptosis of the endothelial cells was still in an early stage. CONCLUSION: alpha-MSH could inhibit the apoptosis of the vascular endothelial cells of the lung in the two-hit ARDS in rats. Therefore, it might have a protective effect on the lung after hemorrhagic shock and endotoxin challenge.